In 2005, 7.6 million people died of cancer out of 58 million deaths worldwide. Based on projections, cancer deaths will continue to rise with an estimated 9 million people dying from cancer in 2015, and 11.4 million dying in 2030 (WHO data). Cancer treatment may involve surgery, radiation therapy, chemotherapy, hormonal therapy, or some combination of these, but presently survival rates for the most of cancer patients is very low. According to World Health Organization, one third of the cancer burden could be cured if detected early and treated adequately. Pathological research provides means for establishing the diagnosis of the most of solid tumors. Although many cases can be classified reliably with current pathological criteria, there is a significant subset of cases in which no consensus can be reached even among expert pathologists. Diagnostic ambiguity has significant adverse consequences for patients. Misclassifying a tumor as benign may be fatal, and diagnosing a benign lesion as malignant may result in significant morbidity. Currently there is no method to definitively resolve these ambiguities. Therefore, there is a clear need for a diagnostic test that could reduce these uncertainties.
Phagocytosis is the process by which cells internalize large particles (typically 0.1 mm diameter), such as bacteria or cell debris. The early stage of phagocytosis can be tentatively divided into distinctive steps: cell membrane binding around the particle, phagosome formation, and internalization of the phagosome. In the process of phagosome formation and internalization, actin cytoskeleton has been proposed to drive these steps to allow engulfment.
Phagocytic cells have been identified in malignant tumors up to a century ago, and, more recently, cells with phagocytic behavior (also defined as cannibalistic behavior) have been detected in tumors of different histology, such as oat cell carcinoma of the lung, breast cancer, bladder cancer, medulloblastoma, gastric adenocarcinomas, melanoma and squamous cell carcinoma of the skin.
We have recently observed that phagocytosis is a character of metastatic melanoma cells able to phagocytose apoptotic cells, plastic beads stained yeasts, and live lymphocytes displaying efficient phagocytic machinery responsible for a macrophage-like activity, while melanoma cells derived from primary lesions did not display any cannibalistic or phagocytic activity. Moreover, cannibal cells can be detected in 100% metastatic melanoma lesions (Lugini et al., 2004; Lugini et al., 2006).
One of the main features of cannibal cells is an increased acidity of lysosomal-like vesicles and an over expression of cathepsin B, a proteolytic enzyme reported to be involved in tumor invasion and metastasis (Sloane et al., 1981). Differently from professional phagocyte-like macrophages, cannibal tumor cells do not utilize structures like ruffles or any pseudopodial movement. Instead, live or dead material that touches the tumor cell's external membrane is immediately endocytosed and digested through a sort of quicksand mechanism that seems not to involve any specific receptor.
These findings have led us to speculate that cannibal cells feed of other cells, perhaps with no particular need of blood-derived nutrient supply, but also that cannibalism of lymphocytes by tumor cells may represent a rudimentary mechanism of tumor immune escape. Moreover, these findings led us to a novel, revolutionary interpretation that cancer cells, in their habit to use other cells for feeding, may behave as unicellular eukaryotes whose unique purpose is to survive in a continuous fighting against other cells and the unfavourable environment. This theory further led us to speculate that amoebas and metastatic cells might share the same framework with the same regulatory elements allowing their surviving in adverse micro-environmental conditions. However, so far no genes have ever been specifically associated with the cannibal behaviour of cancer cells.
The cellular slime mold Dictyostelium discoideum has been previously used as a model organism to study phagocytosis. Mechanisms involved in phagocytosis by Dictyostelium cells are very similar to those used by mammalian phagocytes, and involve the actin cytoskeleton and RacF1, a member of the Rho family of GTPbinding proteins. However, no phagocytosis associated specific proteins have ever been identified in mammals.
It has been recently found that the protein encoded by PHG1A gene was implicated in cell adhesion and phagocytosis in the amoeba Dictyostelium discoideum. This protein belongs to TM9 superfamily and genes encoding TM9 proteins can be unambiguously identified in eukaryotic genomes. The family includes many members in organisms ranging from yeast to plants and human. To mention some example, there are three members of this family in Saccharomyces cerevisiae, Dictyostelium amoebae, and Drosophila flies and four in humans and mice. All of them exhibit a similar overall structure, with a rather variable potential luminal domain followed by a more conserved membrane domain and nine or ten putative transmembrane domains.